Norepinephrine (NE) is the critical pressor determinant in neural regulation of blood pressure, while dopamine (DA) plays an important depressor role via renal and plasma volume mechanisms. Dopaminebeta-hydroxylase (DBH) is the enzyme responsible for the conversion of DA to NE. Great interindividual variation exists in plasma levels of DBH with heritability estimated at 0.9. Polymorphisms in the DBH gene associate with low DBH levels and activity. We reported the extreme example of complete DBH deficiency, a genetic condition in which no functional DBH appears to exist. These patients lack NE and its metabolites both centrally and peripherally but have greatly elevated plasma DA and DOPA. They suffer from severe orthostatic hypotension, hypovolemia, and ptosis of eyelids. Among individuals with low plasma DBH, abnormalities in NE/DA balance might contribute to perturbations in blood pressure and heart rate control. Individuals with low DBH activity might have higher levels of plasma DA under conditions of stress, resulting in hypotension, due to vasodilatation, hypovolemia, or other mechanisms. The relationship of DBH enzyme activity to interindividual variation in cardiovascular control will be evaluated by assessment of baseline and stimulated DBH levels and sympathetic nervous system function in healthy volunteers (selected by DBH genotype) and in patients with orthostatic intolerance, familial dysautonomia, and pheochromocytoma. All subjects will be genotyped for DBH genetic polymorphisms. Study participants will undergo various levels of sympathetic stress in an effort to overwhelm their endogenous DBH capacity and raise plasma DA levels. A pharmacological model of partial DBH deficiency in human subjects will be developed to discover the likely autonomic cardiovascular phenotype. These studies should elucidate the role of DA in blood pressure control in healthy subjects and in certain disease states, and may lead to important advances in their management. [unreadable] [unreadable]